Unraveling the Puzzle: A Case Report Questioning the Causal Relationship Between Subarachnoid Hemorrhage and Microscopic Polyangiitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are small-to-medium-vessel vasculitis, which includes granulomatosis with polyangiitis, microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis. MPA predominantly affects the kidneys and lungs. Subarachnoid hemorrhage (SAH), a life-threatening condition, rarely occurs with AAV. In this case, we present a 67-year-old female who presented with a sudden-onset headache after a recent diagnosis of ANCA-associated renal vasculitis. Kidney biopsy revealed pauci-immune glomerulonephritis, and serum was positive for ANCA along with myeloperoxidase antibody. A computed tomography scan of the head revealed both SAH and intraparenchymal hemorrhage. The patient was managed medically for SAH and intraparenchymal hemorrhage. ANCA vasculitis was treated with steroids and rituximab, and the patient showed improvement.


Introduction
Microscopic polyangiitis (MPA) is a type of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) defined as pauci-immune necrotizing vasculitis of small vessels. Though the exact cause of AAV is not fully understood, the pathogenesis of AAV includes a complex process of immune dysregulation of genetics and environmental factors. The lungs, kidneys, and skin are commonly affected organs, and neurological manifestation has rarely been reported. Mononeuritis multiplex is the most common neurological manifestation of AAV. Stroke, hypertrophic pachymeningitis, massive intracerebral hemorrhage, subarachnoid hemorrhage (SAH), and spinal SAH associated with MPA have been described in case reports [1]. However, per the literature review, it is unclear if MPA has a causal relationship with SAH. Here, we report a rare case of SAH and intraparenchymal hemorrhage concurrent with MPA.

Case Presentation
A 67-year-old female with a recent diagnosis of ANCA vasculitis and past medical history of hypothyroidism, hyperlipidemia, and anxiety presented to our emergency department with a diffuse headache and pressure-like sensation for two hours. Eight days before the presentation, she presented to her primary care physician for fatigue and poor appetite ongoing for six months. She also reported weight loss of about 40 pounds and intermittent low-grade fever for one week. Further lab work revealed a significant increase in creatinine to 2.36 mg/dL (reference range: 0.50-1.1 mg/dL) compared to 0.8 mg/dL two months prior. As a result, she was sent to the emergency room for further workup.
During this hospitalization, the infectious workup, including blood culture, was negative. The immunological workup revealed a positive ANCA titer of 1:80 (normal: <1:20) along with an elevated myeloperoxidase antibody level of 4.6 U/mL (reference: <3.5 U/mL) and elevated C-reactive protein level of 155 mg/dL (normal: <8 mg/dL). The left kidney biopsy revealed findings consistent with ANCA-associated necrotizing crescentic glomerulonephritis (pauci-immune type). As a result, she was treated with intravenous methylprednisolone at a dose of 1 g per day for three days, followed by oral prednisone at a daily dose of 60 mg. Additionally, she received a single dose of 1 g rituximab and was discharged home after nine days of hospitalization. At the time of discharge, she was prescribed prednisone at a daily dose of 40 mg and trimethoprim-sulfamethoxazole for prophylaxis against Pneumocystis jirovecii pneumonia. Her serum creatinine at discharge showed improvement at 1.79 mg/dL. Two days after discharge, she presented to the hospital with a headache for two hours. She described her headache as pressure-like, 7/10 in intensity, started on the occipital area, radiating to her lower neck, and 1 2 3 not relieved by acetaminophen. Her vital signs at presentation were blood pressure of 170/68 mmHg, heart rate of 67 beats per minute, respiratory rate of 20 breaths per minute, temperature of 36.6°C, and oxygen saturation of 100% on room air. The laboratory results at the time of presentation are shown in Table 1.  On physical examination, significant findings included 4/5 strength in bilateral lower extremities, nuchal rigidity, and decreased sensation on the right side of the face. A computed tomography (CT) scan of the head revealed a diffuse left-sided SAH extending to the left ambient cistern, along with a 3.2 × 1.8 cm intraparenchymal hemorrhage at the left posterosuperior parietal lobe without midline shift, as shown in Figure 1. Her Hunt/Hess scale for SAH was grade II. Neurosurgery evaluated the patient and no acute surgical intervention was planned. She was admitted to the medical intensive care unit (ICU) for frequent neurological checks and closer hemodynamic monitoring, and the blood pressure was controlled with a nicardipine drip. A repeat CT of the head was performed 12 hours after the initial scan, which showed stable SAH as the prior CT. A magnetic resonance angiogram (MRA) of the brain revealed a saccular aneurysm measuring 3 × 3 mm involving the paraclinoid segment of the left internal carotid artery, as depicted in Figure 2. A cerebral angiogram was performed, which corroborated the findings of MRA but did not reveal any arteriovenous malformation or fistula. The angiogram also did not show any findings suggestive of vasculitis. Therefore, no neurosurgical intervention was performed. Nicardipine drip was weaned, and her blood pressure remained well controlled on oral medications. After four days, she was transferred out of the ICU to the progressive floor. During this hospitalization, she received a second dose of rituximab, 1 g, 14 days after the first dose. Following one week of hospital rehabilitation, her lower extremities and facial weakness improved, and she was discharged home on a prednisone dose of 40 mg daily.

Discussion
AAV is associated with the presence of antibodies that target neutrophil antigens, primarily leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The exact etiology and pathogenesis of AAV are complex and multifactorial, involving contributions from genetic factors, environmental components, infections, and immunological factors. The precise mechanism underlying cerebral aneurysm formation in MPA is not fully understood. It may be associated with arteritis of small and medium-sized vessels or necrotizing changes [2]. PR3-ANCA and MPO-ANCA have high sensitivity and specificity for AAV, but they can also be present in cases of inflammation, infection, or drug-induced conditions. A positive biopsy supports the diagnosis of vasculitis and is recommended to obtain [3]. In our case, the diagnosis was supported by immunology, kidney biopsy, and clinical manifestations. The clinical manifestations of AAV vary depending on the affected vascular bed. While the lungs and kidneys are the most commonly involved organs, AAV can also affect the upper respiratory tract, skin, heart, and nervous system.
The most common neurological manifestations of AAV include mononeuritis multiplex and hearing loss. A sural nerve biopsy revealed necrotizing vasculitis in 80% of affected patients, and acute axonopathy was seen in nerve conduction studies [4]. Overall, 17-30% of neurological involvement in cases of AAV included the central nervous system, and the most common manifestations included cerebral hemorrhage, pachymeningitis, and non-hemorrhagic cerebral infarctions [4]. These events typically occurred within the first 10 days of admission [2]. However, in the case report by Iyoda et al., cerebral infarction was documented to occur between days 2 and 26 of admission [5], and in the case report by Ku et al., multiple cerebral infarctions were observed after 25 days of admission [6]. In our case, SAH was diagnosed within 11 days of the initial presentation. SAH, regardless of treatment, is associated with a mortality rate of over 50%.